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Non-manifesting carriers (NMCs) of Parkinson’s disease (PD)-related mutations such as  LRRK2  and  GBA  are at an increased risk for developing PD. Dopamine transporter (DaT)-spectral positron emission computed tomography is widely used for capturing functional nigrostriatal dopaminergic activity. However, it does not reflect other ongoing neuronal processes; especially in the prodromal stages of the disease. Resting-state fMRI (rs-fMRI) has been proposed as a mode for assessing functional alterations associated with PD, but its relation to dopaminergic deficiency remains unclear. We aimed to study the association between presynaptic striatal dopamine uptake and functional connectivity (FC) patterns among healthy first-degree relatives of PD patients with mutations in  LRRK2  and  GBA genes .  N  = 85 healthy first-degree subjects were enrolled and genotyped. All participants underwent DaT and rs-fMRI scans, as well as a comprehensive clinical assessment battery. Between-group differences in FC within striatal regions were investigated and compared with striatal binding ratios (SBR).  N  = 26  GBA- NMCs,  N  = 25  LRRK2- NMCs, and  N  = 34 age-matched nonmanifesting noncarriers (NM-NCs) were included in each study group based on genetic status. While genetically-defined groups were similar across clinical measures,  LRRK2 -NMCs demonstrated lower SBR in the right putamen compared with NM-NCs, and higher right putamen FC compared to  GBA -NMCs. In this group, higher striatal FC was associated with increased risk for PD. The observed differential SBR and FC patterns among  LRRK2 -NMCs and  GBA -NMCs indicate that DaTscan and FC assessments might offer a more sensitive prediction of the risk for PD in the pre-clinical stages of the disease.

Aberrant dopamine transporter and functional connectivity patterns in LRRK2 and GBA mutation carriers